Cardiac arrhythmias present a significant health problem. Cardiac arrhythmias include, but are not limited to, ventricular tachycardias, supraventricular tachycardias, and atrial fibrillation. Of these, atrial fibrillation is the most common cardiac arrhythmia. It has been estimated that over one million people in the United States alone suffer from atrial fibrillation. The incidence of atrial fibrillation is expected to increase over the next several decades as populations in the United States and Europe trend older because atrial fibrillation tends to become more common with increasing age.
Arrhythmias after cardiac surgery are a major cause of morbidity and mortality. Tolerability of arrhythmia is less in the postoperative period than for similar arrhythmias in the preoperative period. Hemodynamic instability is more likely due to the possibility of myocardial dysfunction. Cardiopulmonary bypass; injury to the conduction system during surgery; and metabolic and electrolyte abnormalities, especially hypokalemia and hypomagnesemia, contribute to the increased incidence of postoperative arrhythmias. Stress of the surgery with enhanced sympathetic tone and use of inotropic support are added factors. Delayed arrhythmia can occur due to scar-related re-entry.
Atrial fibrillation can be treated with medication intended to maintain normal sinus rhythm and/or decrease ventricular response rates. Specifically, many of the past attempts have been confined to pharmacotherapy, radiofrequency ablation, use of implantable devices, and related approaches. While drug therapy remains a popular route for reducing some arrhythmic events, there has been recognition that systemic effects are often poorly tolerated. Moreover, there is belief that proarrhythmic tendencies exhibited by many drugs can increase mortality in many situations. It would be desirable to have more effective compositions and methods for treating or preventing cardiac arrhythmias.
The invention generally relates to sterilized, acellular extracellular matrix compositions and methods of making such compositions for use in treating or preventing cardiac arrhythmias. More particularly, the invention relates to methods of contemporaneously sterilizing and decellularizing extracellular matrix compositions, as well as the sterilized, acellular compositions resulting from such methods for use in subjects who have undergone heart surgery or had a myocardial infarction to treat or prevent cardiac arrhythmia.
Conventional techniques for sterilizing tissue compositions often alter the properties of the tissue compositions and/or damage important components of the tissue compositions, such as growth factors. Consequently, these conventional sterilization techniques often render tissue compositions unfit for their intended purposes. For example, ethylene oxide is a toxic, mutagenic, and carcinogenic substance that can weaken tissue compositions, reduce the growth factor content of tissue compositions, and denature proteins within tissue compositions. Similarly, conventional steam sterilization techniques are incompatible with the biopolymers of tissue compositions, and gamma radiation causes significant decreases in the integrity of tissue compositions. Although there are known techniques for sterilizing tissue compositions without altering the properties of the tissue compositions, many of these techniques, such as anti-bacterial washes, often fail to completely sterilize the tissue compositions and/or leave residual toxic contaminants in the tissue compositions.
Additionally, when tissue compositions are designed for implantation within the body of a subject, the tissue compositions must often be exposed to a separate, time-consuming decellularization process. This decellularization process is intended to remove cells from the tissue compositions, thereby decreasing the likelihood that the subject's immune system will reject the implanted tissue compositions and/or generate a significant inflammatory response. However, conventional decellularization techniques merely decellularize portions of the tissue compositions such that native cells remain in the tissue compositions following the decelluarization process.
U.S. Pat. No. 7,108,832 (the '832 patent), which is assigned to NovaSterilis, Inc., discloses a method that sterilizes various materials through the use of supercritical carbon dioxide. However, as with other known sterilization methods, tissue compositions that are sterilized using the process disclosed in the '832 patent must be exposed to a separate decellularization process, as described above.
Accordingly, there is a need in the art for a method of sterilizing and decellularizing a tissue composition, such as an extracellular matrix composition. More particularly, there is a need in the art for a method of (a) sterilizing a tissue composition while maintaining the native properties of the tissue composition and (b) decellularizing the tissue composition such that the tissue composition is acellular. There is still a further need for a method of enhancing the incorporation of additives into a tissue composition during sterilization and/or decellularization of the tissue composition for purposes of treating or preventing cardiac arrhythmia.